[2,5-Dihydro 5-phenyl-2-oxo-3-furanyl]amines

ABSTRACT

The present invention relates to compounds of the formula ##STR1## wherein R c  is carboxy, esterified carboxy or amidated carboxy; R 2  is hydrogen or lower alkyl or joins with R a  and R b  and the atoms therebetween to form a fused ring ##STR2## and either R a  is methyl and R b  is ##STR3## or R 2  and R b  and the atoms therebetween form a group ##STR4## wherein R 3  and R 4  are either both hydrogen, or together are propylene, butylene, or with the two atoms to which they are attached form a benzene ring. Methods of manufacture and use thereof in the production of angiotensin converting enzyme inhibitors are disclosed.

This application is a continuation of application Ser. No. 868,227,filed 5/28/86, now abandoned.

The invention relates to a novel process for the production ofangiotensin converting enzyme inhibitors which uses cheaper startingmaterials, less toxic reagents, and allows for simple efficient andinexpensive diasterioisomer separation over the conventional syntheticmeans currently employed. Also within the scope of this invention arethe novel [2,5-dihydro-2-oxo-5-phenyl-furan-3-yl]amine intermediateswhich make the process feasible and the method of their manufacture.

Heretofore, the angiotensin converting enzyme inhibitors, having apartial formula ##STR5## wherein the R groups are as defined below, havebeen prepared by via an expensive, time consuming, multistep syntheticpathway requiring multiple purification steps which culminated in aBorsch Reduction and an extremely difficult diastereoisomericseparation. The details of such methods can be seen in U.S. Pat. Nos.4,410,520 and 4,473,575. A specific synthetic pathway shown in theliterature is given in Drugs of the Future, Vol. 9, No. 5, 1984.

It is an object of the invention to provide a synthetic pathway for themanufacture of angiotensin converting enzyme inhibitors (ACEI) andrelated compounds which is simpler and less costly than the knownmethods.

It is a further object of the invention to provide a synthetic pathwayfor ACEIs which allows for the rapid resolution of the productdiastereoisomers.

It is another object of the invention to provide an ACEI syntheticpathway which avoids the use of many of the highly toxic reagentsrequired in the known synthesis.

SUMMARY OF THE INVENTION

These and other important objects are attained by the instant inventionwhich synthesizes the corresponding ACEI from2-oxo-4-phenyl-trans-butenoic acid by condensation with an appropriateamine, Ry-NH₂, to result in the novel intermediateN-Ry-[2,5-dihydro-2-oxo-5-phenylfuran-3-yl]amine. This compound is thenhydrogenated whereby the furanyl ring becomes saturated, is opened, andthe resulting hydroxy function on the benzyl moiety hydrogenated toresult in a diastereomeric racemic mixture which can be separated intoan essentially pure diastereomer (S,S) by slurrying or recrystallizingthe product from acetonitrile.

While the invention is described mostly in terms of ACEI synthesis, thereaction mechanism is one of general applicability for obtaining acompound of the formula ##STR6## wherein R_(y) is essentially anyradical which will not interfere in the reaction ##STR7## Compound C canbe functionally modified by esterification or amidification as desiredby means well known in the art.

DETAILED DESCRIPTION OF THE INVENTION

Angiotensin Converting Enzyme inhibitors [ACEI] are quickly becoming animportant area of antihypertensive therapy. It is therefore crucial todevelop more efficient, more economic, and safer ways to obtain thesecompounds. The instant invention provides just such a means.

The invention is a new method of producing an angiotensin convertingenzyme inhibitor or precursor thereof of the formula ##STR8## wherein R₁is COOH, an esterified carboxy group or an amidated carboxy group.R_(y), although it can be any organic radical in the generallyapplicable reaction, is essentially a group limited to the formula##STR9## wherein R_(c) is free carboxyl, esterified carboxyl, oramidated carboxyl; and (a) R_(a) is methyl or omega amino lower alkyl;R_(b) is ##STR10## and R₂ is hydrogen or lower alkyl;

(b) R_(a) is methyl or omega amino lower alkyl; and R₂ and R_(b)together along with the atoms to which they are attached form a group ofthe formula ##STR11## wherein n is 0 or 1, and R₃ and R₄ are eachhydrogen or together with the two carbon atoms to which they areattached form a cyclopentane, cyclohexane, or benzene ring;

(c) R₂, R_(a), and R_(b), together with the atoms therebetween, form afused ring of the formula ##STR12##

(d) R₂ is hydrogen or lower alkyl and R_(a) and R_(b), together with theatoms therebetween, form a group of the formula ##STR13## wherein m is 1or 2; X is O, S, SO, SO₂ or CH₂ ; and R₅ and R₆ are each hydrogen, ortogether with the two carbon atoms to which they are attached form abenzene ring which is unsubstituted or mono or disubstituted by asubstituent selected from lower alkyl, lower alkoxy, lower alkanoyloxy,hydroxy, halogen or trifluoromethyl or the two substituents together arelower alkylenedioxy. The benzene ring formed by R₅ and R₆ may also besaturated so as to result in the cyclohexyl analogs. Whenever used,"lower" means up to 4 members.

Essentially, the method entails reacting an amine of the formula##STR14## with β-keto-4-phenyl-but-3-ene-oic acid in the presence of analcohol, preferably a lower alkanol, more preferably ethanol, to obtaina novel intermediate of the formula ##STR15## These intermediates arealso within the scope of the invention. A similar reaction usinganilines instead of a compound of formula F is disclosed in J. Org.Chem. 33, No. 10, pp. 3991-3993 (1968).

The intermediate G is then catalylically hydrogenated, in the additionalpresence of an alcohol, preferably a lower alkanol, more preferablyethanol, to a compound of the formula ##STR16## The hydrogenationreaction saturates the double bond in the 2,5-dihydro furan ring andcauses the lactone bond to break, thereby opening the ring. Since thisresults in a benzylic hydroxy function, the hydrogenation continues sothat the product of formula H is obtained. Although most anyhydrogenation catalyst will suffice a Pd/C catalyst is especiallypreferred.

A surprising and important feature of the invention is that theresolution of the S,SR racemic mixture into the desired S,S compounds offormula D is simply and quickly accomplished by slurrying the mixturewith or recrystallizing it from acetonitrile. The S,S diastereomer isgenerally obtained obtained in greater than 98% optical purity.

When the desired end product (formula D) has R₁ ═COOH and the R_(c)group is as desired in the starting material, the synthesis is complete.However, if R_(c) was originally esterified or amidated and the desiredproduct has R_(c) as a free carboxyl group, reaction with HCl will yieldthe desired product. If the desired product is to have R_(c) as anesterified or amidated group and R₁ as an esterified group, the desiredR_(c) group should be in the R_(y) -NH₂ compound. Then the product ofthe crystallization or slurrying step can be reacted with the desiredalcohol, preferably a lower alkanol, most preferably ethanol, in thepresence of SOCl₂ to yield the desired product. Further treatment ofthis product with about 4N HCl at about 50° C. for about 1 hour willselectively free the R_(c) carboxyl group without affecting the R₁ester. Still further treatment with acid will free the R₁ carboxyl groupas well.

Preferred esterification groups for the R₁ carboxyl group arepharmaceutically acceptable alcohols which esters may be cleaved underphysiological conditions. In any case when the free R₁ carboxyl group isdesired, any alcohol which is otherwise non reactive with the rest ofthe molecule and readily removable by known means is suitable as theesterification group for R₁. Lower alkanols are especially preferred,most especially ethanol.

In the case where the free R_(c) carboxyl group is desired, anyesterification and amidification group for the R_(c) carboxyl group issuitable, provided it can be readily removed. In the case where R₁ is toremain esterified, any esterification or amidification group is suitableprovided the R_(c) ester or amide can be selectively removed vis-a-viethe R₁ ester group. When the R_(c) carboxyl group is to remainesterified or amidated, these groups should be pharmaceuticallyacceptable. Preferably, the esters are of lower alkanols most suitablyethanol. Preferably, the amides are of ammonia, a lower alkyl amine or adi lower alkyl amine.

Preferred R_(y) groups include ##STR17## wherein R is OH, an ester groupor an amide group. It is preferable that these ester and amide R groupsbe cleavable under physiological conditions and that they be derivedfrom pharmaceutically acceptable alcohols and amines. However, where theR group is to be OH in the final product to be administered, other esterand amide groups are also suitable.

Most preferably the R group is OH.

Most preferably, the products of the instant process are of formula Dwherein R₁ is COOH and R_(y) is ##STR18## and the correspondingcompounds of formula G above.

In addition to the above, lisinopril, having the formula ##STR19## canalso be made by the described process starting from ##STR20## where theprimary amine is suitably protected.

The invention will be more specifically understood in terms of thefollowing examples, which are exemplary only and do not limit the scopeof the invention.

EXAMPLE 1

Compound numbers in this Example are keyed to the reaction scheme setforth at the end of the Example.

Preparation of: Ethyl 3-[(25dihydro-2-oxo-5-phenyl-5S-3-furanyl)amino]2345 tetrahydro 2 oxo 3S 1benzazepine 1 acetate (compound 3).

To a solution of 0.935 g. (0.0055 moles) of 2 oxo-4 phenyltrans-3-butenoic acid in 8-10 mL of cold ethanol was added dropwise withstirring at 0° C. a solution of 1.3 g (0.005 moles) of Ethyl 3amino-2,3,4,5-tetrahydro-2-oxo-1-3S) benzazepine 1-acetate. When theaddition was complete the reaction mixture was stirred at 20° C. for 1hour then allowed to warm to ambient temperature. After 20-48 hours theproduct precipitates out as a thick slurry and can be filtered to yieldbetween 60-90% of the desired product depending on reaction time andtemperature. m.p. 144°-146° C. (crude). The product can berecrystallized--mp 146°-148° C.

PREPARATION OF COMPOUND (4)

The unsaturated amino lactone compound 3 (25 g, 0.06 mol) was suspendedin ethanol (1500 mL) and to this was added 4Å molecular sives (50 g) and5 g of Pd/C 5%. The mixture was hydrogenated at ambient temperature forapproximately 20 hours until the theoretical amount of hydrogen wasconsumed. The reaction mixture was filtered (to remove the catalyst andmolecular sives) and the filter cake was washed with fresh ethanol (˜1L). The combined filtrates were refiltered through celite andconcentrated to yield 25 g of a white solid (crude product). The crudeproduct was recrystalized from acetonitrile (˜200 mL, 80° C.), andcooled to yield 8.3 grams (1st crop) of the SS diasteromer compound 4,mp. 185°-186° C. Rot. [α]D²⁵ 1% in Ethanol was ˜-156.87°.

PREPARATION OF COMPOUND 5 (THE DIESTER)

To a suspension of compound 4 [8.0 g (0.0188 mole) in ethanol (˜80 mL)cooled to 6° C.] was added dropwise thionyl chloride 3.2 mL (4.88 g,0.41 mol) to give a clear solution. The reaction mixture was refluxedfor ˜40 hours after which the reaction mixture was monitored by TLC(Tol:ETOAC: 1:1) and ETOAC, MEOH, NH₄ OH (17:3:3) and proved to be >90%complete. The reaction mixture was evaporated to dryness to yield thecrude product which by HPLC analysis was >91% pure SS diasteromer ofcompound 5.

PREPARATION OF COMPOUND 6 (ALKALINE CONDITIONS)

To a solution of diester 5 (1 g, 0.002 mol) in ethanol (10 mL) was addeda solution of sodium carbonate (212 mg, 0.002 mol) in 8 mL of waterfollowed by a solution of sodium hydroxide 1.8 mL of 1M (0.0018 mol).The reaction mixture was stirred at ambient temperature and monitored byHPLC (C18 column, using a water→methanol gradient over 20 minutes). Whenthe reaction was complete, the ethanol was removed under vacuum and theaqueous residue was extracted 2×'s with diethyl ether (to remove anyunreacted starting material) and the aqueous layer was then adjusted toa pH of 4.3 with 12N.HCl. The aqueous layer was extracted exhaustivelywith methylene chloride which were combined, dried (Na₂ SO₄), andconcentrated to yield ˜400 mg (˜46%) of the desired compound 6.

PREPARATION OF COMPOUND 6 (ACID CONDITIONS)

A suspension of the diester 5 (R=Et) (0.5 g, 0.01 mol) in 10 mL of 4N.HCl was heated to 50° C. for about ˜4 hours after which time thereaction mixture became homogenious and was monitored by HPLC(water/MEOH 25:75) to yield >88.5% of the desired product CGS 6. Thereaction mixture was cooled and the product crystalized out of solution.The crystals were filtered and dried to yield the a crude productcompound 6 which by HPLC was >96% pure (impurities were ˜1% diacid and2% diester).

PREPARATION OF COMPOUND 7

To a suspension of Compound 6 (1 g, 0.002 mol) in ethanol (about ˜10 mL)was added 4 mL of a 1.9N solution of potassium hydroxide. The reactionmixture was stirred at ambient temperature for 1 hour, warmed to 50° C.for 10 minutes then cooled. The ethanol was removed under vacuum and thepH of the remaining aqueous solution was adjusted to pH 1 with 12N--HCland the desired product compound 7 precipitated out of solution. Theproduct was filtered, washed with acetone, and dried to yield 600 mgproduct (mp. 278°-280° C.). ##STR21##

EXAMPLES 2-4

Example 1 was followed except that the R group in compound 1 was methyl,tert-butyl, and hydrogen respectively. In the case where R=hydrogen,hydrogenation of compound 3 and recrystallizing from acetonitrile yieldscompound 7 directly.

I claim:
 1. A compound of the formula ##STR22## wherein R_(c) is carboxyl, lower alkoxycarbonyl, carbamoyl, N-mono lower alkyl carbamoyl, or N,N-di-lower alkyl carbamoyl; and(a) R_(a) is methyl or omega amino lower alkyl; R_(b) is ##STR23## and R₂ is H or lower alkyl; or (b) R_(a) is methyl or omega amino lower alkyl; and R₂ and R_(b) together along with the carbon and nitrogen atoms to which they are attached form a group of the formula ##STR24## wherein n is 0 or 1; and R₃ and R₄ are each hydrogen, or together with the two carbon atoms to which they are attached form a cyclopentane, cyclohexane, or benzene ring; or (c) R₂, R_(b) and R_(a) together with the atoms therebetween form a fused ring of the formula ##STR25## or (d) R₂ is hydrogen or lower alkyl; and R_(a) and R_(b), together with the atoms therebetween form a group selected from ##STR26## wherein R'₅ and R'₆ are each independently hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, halogen, or trifluoromethyl, or R'₅ and R'₆ are together lower alkylenedioxy; X is O, S, CH₂, SO, SO₂ ; n=1 or 2; and ring A is phenyl or cyclohexyl. 